Prof. Jae Heon, Jeong/R2 Cheol Hyun, Lee J of Clinical oncology, Vol 31 Number 4, Feb.1, 2013

Introduction  The receptor tyrosine kinase MET, its ligand hepatocyte growth factor (HGF), and the vascular endothelial growth factor (VEGF) signaling pathway seem to play critical roles in the development and progression of castration-resistant prostate cancer (CPRC).  Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with potent activity against MET and VEGF receptor 2 (VEGFR2). In vivo, cabozantinib suppresses MET and VEGFR2 signaling, rapidly inducing apoptosis of endothelial cells and tumor cells, resulting in tumor regression in a variety of xenograft models.

Introduction  Purpose of this study Evaluated the activity of cabozantinib in patients with castration- resistant prostate cancer (CRPC) in a phase II randomized trial with an expansion cohort.

Patients and Methods  Patients CRPC with measurable disease by RECIST with PD. One prior standard chemotherapy regimen completed at least 4 weeks.  Study design Patients with SD at 12 weeks. (cabozantinib or placebo) Randomly assigned patients were observed until progression. Patients restarted on cabozantinib after first progression on placebo were observed until subsequent progression.  Drug administration Patients received an initial daily dose of cabozantinib 100mg.  Study assessments Radiographic soft tissue, bone scan, PSA, bone marker(CTx, tALP)

Results

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Results

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Results

Discussion  In this study, cabozantinib demonstrated dramatic and rapid Effects on bone scan lesions in a high proportion of patients.  Other study results suggest that selectively targeting VEGFR alone, VEGF alone, MET alone, or the tumor cells and/or osteoclasts individually does not result in the bone scan effects observed in patients with CRPC treated with cabozantinib.  True benefit will only be determined from randomized trials, and phase III studies have been initiated to evaluate the effect of cabozantinib on morbidity and mortality in patients with CRPC with bone metastases.

Conclusion  Cabozantinib has substantial antitumor activity in patients with advanced CRPC with manageable toxicity consistent with other tyrosine kinase inhibitors targeting multiple pathways.  These results indicate a potential cooperative role for c-MET and VEGF signaling in the progression of CRPC and suggest that dual targeting of tumor and microenvironment may lead to an improved outcome for patients with CRPC.

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